MODERN

PHARMACEUTICS
COMPRESSION AND
COMPACTION

Presented by
PUJITHA R,
M.Pharmacy I Sem
Department of Pharmaceutics,
College of Pharmacy, Madras Medical College, Chennai

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CONTENTS
✓ Definitions
✓ Compaction
✓ Physics of tablet compression
✓ Consolidation
✓ Effect of friction
✓ Distribution of forces
✓ Compaction profiles
✓ Solubility
✓ References
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 DEFINITIONS
➢ COMPRESSION is the reduction in bulk volume of material due to
displacement of gaseous phase by applied pressure.
➢ CONSOLIDATION is the increase in the mechanical strength of material
resulting from particle-particle interactions.
➢ COMPACTION can be defined as the compression and consolidation of a
particulate solid–gas system as a result of an applied force, forming a compact but
porous mass of a definite geometry.
Transformation of powder into coherent specimen caused by applied pressure
is compaction.
Compaction = Compression + Consolidation 3
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➢ COMPRESSIBILITY is the ability of a material to undergo a reduction in volume as
a result of an applied pressure and is represented by a plot of tablet porosity against
compaction pressure.
➢ COMPACTIBILITY is the ability of a material to produce tablets with sufficient
strength under the effect of densification and is represented by a plot of tablet tensile
strength against tablet porosity
➢ TABLETABILITY is the capacity of a powdered material to be transformed into a
tablet of specified strength under the effect of compaction pressure and is represented
by a plot of tablet tensile strength against compaction pressure.

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POWDER COMPRESSION
• It is defined as the reduction in a volume of powder due to the application of forces.
• During compression, due to increase in proximity of particles, surfaces bonds are formed between the
particles. The bonds involved are,
- Mechanical interlocking
- Inter particulate attraction forces
- Solid bridges
• These bonds provide coherence to the powder, i.e., a compact is formed.
Evaluation of compression behavior:
The procedures used in research and development work to evaluate the compression behavior of
particles
and the mechanisms of compression involved in the volume reduction process are of two types:
➢ Characterization of ejected tablets;
➢ Characterization of the compression and decompression events.
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VARIOUS STEPS INVOLVED IN COMPACTION OF POWDERS
UNDER AN APPLIED FORCE

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TABLETS:
• Tablets are compressed solid dosage forms consisting of active ingredients and
suitable pharmaceutical excipients for oral administration.
• They may vary in size, shape, weight, hardness, thickness, disintegration and
dissolution characteristics and in other aspects.
• They may be classified according to their
method of manufacture as
➢ Compressed tablets
➢ Molded tablets

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INTRODUCTION:
• Tablets constitute about 70-80% of all pharmaceutical dosage forms.
• They are manufactured by
➢ Granulation
▪ Dry granulation : suitable for drugs that are sensitive to moisture and heat.
▪ Wet granulation : suitable for drugs that are stable to moisture and heat.
➢ Direct compression
▪ Powder compression : suitable for drugs that are sensitive to moisture and heat, fill
material processing, good flowability and compressibility.
▪ Crystal compression : suitable for drugs with proper crystal form and good flowability.
• Invention of tableting machine: In 1843 by William Brockedon.

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Method of Granulation:
The wet granulation process is the most conventional technique in the manufacture of tablets and was
once thought to yield tablets that dissolve faster than those made by other granulation methods. The
limitations of this method include—
(i) Formation of crystal bridge by the presence of liquid,
(ii) The liquid may act as a medium for affecting chemical reactions such as hydrolysis, and
(iii) The drying step may harm the thermo-labile drugs.
The method of direct compression has been utilized to yield tablets that dissolve at a faster rate. One
of the more recent methods that have resulted in superior product is Agglomerative Phase of
Communition (APOC). The process involves grinding of drugs in a ball mill for time long enough to
affect spontaneous agglomeration. The tablets so produced were stronger and showed rapid rate of
dissolution in comparison to tablets made by other methods. The reason attributed to it was an increase in
the internal surface area of the granules prepared by APOC method. 10
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 EQUIPMENTS FOR TABLET COMPRESSION
TABLET PRESS MACHINE:-
It is an electro mechanical device that uses compression force to transform powder
into tablets of uniform size and thickness.
PRINCIPLE:-
The basic principle behind the tablet compression machine is hydraulic pressure.
This pressure is transmitted unreduced through the static fluid. Any externally applied
pressure is transmitted via static fluid to all the directions in the same proportion.

TYPES OF MACHINES FOR TABLET COMPRESSION:-

✓ Single station tablet press
✓ Multi-station tablet press
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 BASIC COMPONENTS OF TABLET COMPRESSION MACHINE
1. HOPPER: Holds the feeding material that are to be compressed.
2. DIE: The cavity that defines the size and shape of the powder.
3. DOSING PLOW: Pushes a small, precise amount of product into the die cavity.
4. PUNCHES: Compresses the granulating material within the die.
5. TURRETS: Holds the upper and lower punches (Heart of the tablet compression
machine).
6. CAM TRACK: Guides the movement of the punches.
7. EJECTION CAM: Pushes the bottom punch upwards, ejecting the finished tablet from the
die cavity.

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1. SINGLE STATION TABLET PRESS:-

A single station tablet press machine is the

simplest tableting equipment. It is also called as single
punch or eccentric press.

It can be operated manually or an electric motor

can be incorporated. The compression force of the
machine is due to the upper punch only and the lower
punch remains stationary during this period. This
shows that the working process is similar to
hammering.

The single punch tablet press usually produces 60-

85 tablets/min.
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PARTS OF THE SINGLE PUNCH MACHINE:-
i. HOPPER: This is the section to put all the material to be compressed either manually
or using other mechanical means.
ii. DIE CAVITY: This determines both the size and shape of the tablet.
iii. PUNCHES: These machines have upper and lower punches that press the material
within the die cavity into a desired tablet.
iv. TABLET ADJUSTER: It helps to control the size and weight of the tablet by
regulating the amount of powder intended to compress.
v. EJECTION ADJUSTER: It makes it easy to eject the tablets from the die cavity of
the tableting machine.

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WORKING MECHANISM OF THE SINGLE PUNCH MACHINE:-
The working cycle is as follows
➢ Filling
➢ Weight adjustment
➢ Compression
➢ Ejection

(i) FILLING:-
This process involves the transfer of granules into position for tablet compression. The
upper die moves upwards and the lower die moves downwards and is responsible for the
volume of the die cavity.

(ii) WEIGHT ADJUSTMENT:-

The lower punch is raised to the required level in the die to get the required weight of
granules in the punch die cavity. Excess granules are scraped off from the surface of the die
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(iii) COMPRESSION:-
During this stage, the top and bottom punch come together by pressure within the die to
form the tablet and move between two large wheels called compression rolls. These rolls
push the punches towards the die to form the tablet.

(iv) EJECTION:-
This process involves removal of tablet from the lower punch die station. In this stage,
the upper punch retracts from the die and rises above the turret table. The lower punch rises
in the die, which in turn pushes the tablet upward to the top surface and out of the cavity.

ADVANTAGES OF SINGLE PUNCH TABLET MACHINE:-

In most cases, this machine can be used to make chewable and effervescent tablets.
a) Easy to operate, no need for advanced training.
b) Space saving small structure.
c) Can manufacture tablets with odd shapes.
d) Reduces weight variations since it uses high pressure.
e) Operates with low noise.
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2. MULTI-STATION ROTARY
PRESS :-
A multi-station press tablet
manufacturing machine, also
known as rotary machine is one of
the most popular equipment in the
pharmaceutical industry due to its
high production capacity.
The name rotary tablet press is
due to the rotating tableting
assembly. In these machines, it is
the rotation speed of the turret and
number of stations that determine
the production capacity.
Used to produce about 8,000 to
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WORKING MECHANISM OF A ROTARY TABLET PRESS :-
The three steps include:
➢ Filling
➢ Compression
➢ Ejection

(i) FILLING:
The material to be compressed is placed in the fixed hopper and then, it is fed to the
several dies simultaneously.
(ii) COMPRESSION:
Like in case of the single punch machines, the punches exert the required magnitude
of force to convert powder or granules to tablets. Depending on the design of the
machine, the process may involve pre-compression and mainly compression.

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(iii) EJECTION:
After full compression, the automatic tablet press machine will withdraw the upper
punch as the lower punch rises. This brings the tablet above the die’s surface.

ADVANTAGES OF MULTIPLE STATION TABLET PRESS MACHINE:-

a) Cost efficient than single punch tablet press.
b) Suitable for continuous operations where bulk production of tablets is required
depending on the design and configuration of the tableting machine.
c) Automated systems, hence eliminates most human interventions and thus ensures
consistency and accurate tableting processes.
d) Guarantee independent control of both hardness and weight.

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Rearrangement/ Repacking can also occur on applying more force. Particles undergo certain types of
deformations.
The two types of deformation are:
1. Elastic deformation: On removal of force, the solids come back to their original place called elastic
deformation. Usually all solids undergo elastic deformation. Eg: Paracetamol.
2. Plastic deformation: They won’t come back to their original volume, complete reduction in the bulk volume
takes place [When shear strength of particles is less than the tensile (breaking strength) of the particles].
Brittle fracture : Shear strength is more than the tensile strength.
For proper compression to occur, the tablet should be plastic i.e., capable of permanent deformation and it should
also exhibit certain degree of brittleness.
Accordingly, if the drug is plastic, the excipients chosen should be brittle (Lactose, Calcium phosphate) and
if the drug is brittle, then the excipients should be plastic (Microcrystalline cellulose).

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Stages involved in the compression of powder are:

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 CONSOLIDATION
An increase in the mechanical strength of material resulting from particle or particle interaction is
called consolidation.
Consolidation process is of two types:
1. Cold welding:
When the surface of two particles approach each other (<50 nm) closely enough, their free surface
energies result in attractive force, this process known as cold welding.
2. Fusion bonding:
Because of the roughness of the particles, the actual area involved in bonding may be small. Contacts
of particles at multiple points upon application of load, produces heat which causes fusion or melting.
If this heat is not dissipated, the local rise in temperature could be sufficient to cause melting of
contact area of particles . Upon removal of load it gets solidified giving rise to fusion bonding and
increase the mechanical strength of mass. 24
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FACTORS AFFECTING CONSOLIDATION
Both cold and fusion welding, the process is influenced by several factors like
❖Chemical nature of the materials
❖Extent of the available surface
❖Presence of surface contaminants
❖Inter-surface distances
❖Degree and type of crystallinity.

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 PHYSICS OF TABLET COMPRESSION
In pharmaceutical tableting, an appropriate volume of granules in a die cavity is compressed
between an upper and lower punch to consolidate the material into a single solid matrix, which
is subsequently ejected from the die cavity as an intact tablet. The subsequent events that occur
in this process are:
1. Transitional repacking/particle rearrangement
2. Deformation at the point of contact
3. Fragmentation
4. Bonding
5. Deformation of solid body
6. Decompression
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1. TRANSITIONAL REPACKING OR PARTICLE REARRANGEMENT:
❑ The particle size distribution and shape of granules determines initial shapes of
compression, the punch and particle movement occurs at low pressure.
❑ During this stage, particle moves with respect to each other and smaller particles enter
the voids between the larger particles. As a result, the volume decreases and bulk density
of granules increases.
❑ Spherical particles undergo less rearrangement than irregular particles as spherical
particles tend to assume a close packing arrangement initially.
❑ To achieve a fast flow rate required for high speed presses the granules is generally
processed to produce spherical or oval granules, thus particle rearrangement and energy
expended in rearrangement are minor considerations in the total process of compression.
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2. DEFORMATION AT THE POINT OF CONTACT:
❑ When a stress is applied to a material, deformation (change of form) occurs. If the deformation disappears
completely (return to its original shape) upon the release of stress, it is known as elastic deformation.
❑ If the deformation does not completely recover after the release of stress, it is known as plastic
deformation. Original state Elastic
regained deformation
Stress Removal of
Deformation
applied stress
Original Plastic
state lost deformation

❑ The force required to initiate plastic deformation is known as yield stress.

❑ When the particles of granulation are so closely packed so that no further filling of the voids can occur, a
further increase of compressional force causes deformation at the point of contact.
❑ Both plastic and elastic deformation may occur although only one type predominates for a given material.
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3. FRAGMENTATION
❑ As the compressional load increases, the deformed particle starts undergoing fragmentation.
❑ Because of the high load, the particle breaks into smaller fragments leading to the formation of
new bonding areas.
❑ The fragments undergo densification with infiltration of smaller fragments into voids.
❑ Fragmentation do not occurs when applied stress
- is balanced by a plastic deformation
- change in shape
- sliding of groups of particles (viscoelastic flow)
❑ Increases the number of particles and forms new clean surfaces that are potential bonding areas.
❑ Some particles undergo structural breakdown known as brittle fracture.

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4. BONDING OF PARTICLES
❑After fragmentation as the pressure increases formation of new bonds between the
particles at the contact area occurs.
❑This favoring for the increasing mechanical strength of a bed of powder when subjected
to rising comprehensive forces can be explained by the following bonding theories.
❑Bonding/ Consolidation mechanism
There are three theories about the bonding of particles in the tablet by compression :
• Mechanical theory
• Inter-molecular force theory
• Liquid film surface theory

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(i) THE MECHANICAL THEORY:
❖Occurs between asymmetric shaped particles.
❖This theory proposes that, under pressure the individual particles undergo
elastic/plastic deformation and that the edges of particles intermesh forming
mechanical bond.
❖Mechanical interlocking is not a major mechanism of bonding in pharmaceutical
tableting.

Total energy of compression = energy of + heat released + energy absorbed for

deformation each constituent

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(ii) INTERMOLECULAR FORCE THEORY:
❖The molecules at surface of solids have unsatisfied forces which interact with other
particle in true contact.
❖It states that, under compressional pressure the molecules at the points of true contact
between new clean surfaces of the granules are close enough so that Vander waal’s
forces interact to consolidate the particles
❖OH group may also create hydrogen bond between molecules.eg. Microcrystalline
cellulose is believed to undergo significant hydrogen bonding during tablet
compression.
❖This theory and liquid surface film theory are believed to be the major bonding
mechanisms in tablet compression.
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(iii) LIQUID – SURFACE FILM THEORY :
❖Due to the applied pressure, the particles may melt (due to lowering of melting point) or
dissolve (due to increased solubility).
❖A thin liquid film form which bond the particles together at the particle surface.
❖Many pharmaceutical formulations require a certain level of residual volume of
moisture to produce high quality tablets.
❖The energy of compression produces melting of solutions at the particles interface
followed by subsequent solidification or crystallization thus in the formation of bonded
surfaces.
❖This is the major bonding mechanism involved in the tablet compression.

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5. DEFORMATION OF THE SOLID BODY
❑When applied pressure is increased, bonded solid is consolidated towards a limiting density
by plastic or elastic deformation.
6. DECOMPRESSION:
❑The success or failure to produce an intact tablet depends on the stress induced by elastic
rebound and the associated deformation process during compression.
❑As the upper punch is withdrawn from the die, the tablet is confined to the die by radial
pressure.
❑As the movement of the tablet is restricted by the residual die wall pressure and the friction
within the die wall, the stress from the axial elastic recovery and the radial contraction
causes capping of the tablet unless the shear stress is relieved by the plastic deformation.
❑The rate of decompression can also effect the ability of the compact to consolidate.
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❑Based on liquid –surface film theory the rate of crystallization or solidification and should
have effect on the strength of bounded surface
❑High decompression rate should result in high rate of crystallization, typically slower
crystallization result in stronger crystals.
❑Stress relaxation of plastic deformation is time dependent.
❑Materials having slow rate of stress relaxation crack in the die upon decompression.
❑The rate of stress relief is slow for Acetaminophen, so cracking occurs within the die
whereas with MCC, the rate is rapid and hence intact tablets are produced.
❑A slower operational speed provides more time for relaxation, hence can prevent cracking.
❑A tablet press that provides pre-compression allows some stress relaxation before final
compression.
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7. EJECTION
❑As the lower punch raises and pushes the tablet upwards, there is a continued residual die
wall pressure and considerable energy may be expanded due to die-wall friction.
❑As the tablet is removed from the die, the lateral pressure is relieved and the tablet undergoes
elastic recovery with an increase (2-10%) in the volume of that portion of the tablet removed
from the die.
❑During ejection, that portion of the tablet within the die is under strain, and if it exceeds the
shear strength of the tablet, the tablet caps adjacent to the region in which the strain has been
just removed.
❑Three forces are necessary to eject a finished tablet:
i. Peak force required to initiate ejection.
ii. Small force required to push tablet upto die wall.
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iii. Decline force as tablet emerges from die.
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 The parameters that attributes to the quality of the tablets such as Target weight,
Weight uniformity, Content uniformity, Hardness, Thickness, Tablet porosity, Friability are:
1. Compression speed
2. Force Pre-compression
3. Force main compression
4. Force Feed frame type and speed
5. Hopper design, height
6. Depth of fill
7. Punch penetration depth

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 FORCES INVOLVED IN THE COMPRESSION
1. Frictional force :-
• Frictional forces are two types: inter-particulate friction and die wall friction.
• Inter-particulate friction forces occur due to particle - particle contact and it is more significant at low
applied load.
These forces are reduced by using Glidants. Eg: Colloidal silica (fumed silica).
• Die wall friction forces occur from material pressed against die wall and moved it is dominant at high
applied load.
These forces are reduced using Lubricants. Eg: Magnesium stearate.
2. Distribution forces :-
• Most investigations of fundamentals of tableting have been carried out on single punch press or even
isolated dies and punches with hydraulic press.
• A force is applied on top of cylinder of powder mass consider single isolated punch.
• When force is being applied to top of a cylindrical powder mass, the following basic relationship applies,
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since there must be an axial (vertical) balance of forces.
 FA = FL + FD
Where,
FA = Force applied to upper punch
FL = Force transmitted to lower punch
FD = reaction at die wall due to friction at surface

3. Compaction force: Because of difference

between applied force at upper punch which affects
material close to lower punch is called mean
compaction force (FM)

𝐅𝐋
FM = FA +
𝟐
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4. Radial force :

• As compressional force is increased, any repacking of tableting is completed forming a

single body mass.
• Classical friction theory can be applied to obtain a relationship between axial frictional
force FD and radial force FR as
FD = µW . FR
where
µW is coefficient of die wall friction.
• Degree of lubrication is compared to measure FA & FD and determine the ratio of 𝐅𝐋/FD.
This is called the coefficient of lubrication efficiency or R value.
• It approaches 1 for perfect lubrication and in practice, as high as 0.98 can be achieved.
• Values below 0.8 indicate poor lubrication.
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5. Poisson’s ratio of material:
• When force is applied on vertical direction which result in decrease in height (∆H) for
unconfined solid body, the expansion is in horizontal direction (∆D).
• This ratio of two dimensional changes is known as Poisson’s ratio.
λD = (∆D) / (∆H)
• The material is not free to expand in horizontal plane because it is confined in die at the
same time a radial die wall force (FR) develops perpendicular to die wall surface.
• High Poisson’s ratio → higher FR value.
• The Poisson’s ratio is a characteristic constant for each tablet.

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6. Ejection force:
• Radial die wall forces and die wall friction also affects the ease with which the compressed
tablet is ejected from the die by breaking tablet/die wall adhesion.
• The force necessary to eject the finished tablet is known as ejection force. .
• The force necessary to eject a finished tablet follows a distinctive pattern of three stages.
➢ The first stage involves distinctive peak force required to initiate ejection, by breaking of
tablet/die wall adhesions.
➢ A smaller force usually follows, that is required to push the tablet up the die wall.
➢ The final stage is marked by a decline in force of ejection as the tablet emerges from the
die.
• Variation in this pattern also occurs in ejection force when lubrication is inadequate and/or
slip-stick conditions occurs between tablet and die wall.
• Well lubricated systems have been shown to have smaller values of FE .
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 PROPERTIES OF TABLET INFLUENCED BY COMPRESSION
1. DENSITY AND POROSITY:
❑ The apparent density of a tablet is exponentially related to applied pressure or compressional force until the
limiting size of the material is achieved.
D=m/V
Where, D - Density of particles
m - mass of powder
V - Volume
❑ Apparent density of tablet of exponentially related to applied pressure.
❑ As compressional force increases, the density of tablet also increases as a result of decrease in bulk
volume.
❑ As the porosity and apparent density are inversely proportional, the plot of porosity against log of
compression force gives linear plot with a negative slope.
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2. HARDNESS AND TENSILE STRENGTH:
❑ A linear relationship exists between tablet hardness and the logarithm of applied pressure, except at high
pressure.
3. SPECIFIC SURFACE AREA:
❑ Specific surface area initially increases to a maximal value when the force increases, indicating the
formation of new surfaces due to fragmentation of granules.
4. DISINTEGRATION:
❑ Usually as applied pressure used to prepare a tablet is increased, disintegration time increases
(lactose/aspirin alone).
❑ Frequently, there is exponential relationship between disintegration time and pressure (Aspirin-Lactose).
❑ In some formulations, there is minimum value when applied pressure is plotted against log of
disintegration time.
❑ For tablets compressed at low pressure, there is a large void and the contact of starch grains in the inter-
particulate space is discontinuous, thus there is a lag time before the swelling of the starch grains due to
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surrounding tablet structure.
❑ For tablets compressed at certain applied pressure, the contact of starch grains is continuous with the tablet
structure and the swelling of starch immediately exerts pressure, causing most rapid disintegration.
❑ For tablets compressed at pressures greater than that producing minimum disintegration time for the
penetration of water into the tablet, an increase in disintegration time is observed.
5. DISSOLUTION:
❑ The curve obtained by plotting compression force versus rate of dissolution can take one of the 4 possible
shapes shown.

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 FACTORS AFFECTING THE STRENGTH OF
TABLETS

✓ Particle size
✓ Moisture content
✓ Lubricants
✓ Applied pressure
✓ Binders
✓ Entrapped air
✓ Porosity
✓ Particle shape

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1. PARTICLE SIZE
➢ A decrease in particle size resulted in increase in tablet strength, the general equation is
Fc =K×d²
Where,
k - constant
Fc - hardness of compact
d - diameter of particle
2. APPLIED PRESSURE
➢ At higher forces due to fragmentation, new surfaces are formed causing an increase in surface
area. hence more area is available for bond formation, hence more will be hardness of the
compact.
➢ According to Balshin equation, Fc = Fco × Vr
Where,
Fco - strength of tablet
Vr - relative volume
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3.MOISTURE CONTENT
➢ A small proportion of moisture content is desirable for the formation of a coherent tablet.
➢ Several effects seen by the presence of moisture content are
- die wall lubrication
- inter-particulate lubrication
- expression of interstitial liquid to the die wall
➢ At low moisture content, there will be increase in die wall friction due to increased stress ratio,
hence hardness will be poor.
➢ At high moisture level, the die wall friction is reduced owing to lubricating effect of moisture.
➢ Further increase in moisture content, there will be decrease in compact strength due to reduction
in inter-particulate bonds

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4. LUBRICANTS
➢ Lubricants assist particle movement by reducing particle - die wall friction.
➢ The lubricants is spread over the surface of particles and hence reduces the bonding
between the particles.
➢ It has been reported that increase in the quantity of lubricant resulted in reduction of
the mechanical strength of compressed tablets.
➢ Eg: Stearic acid,
Magnesium stearate,
Calcium stearate,
Boric acid, etc.,

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5. BINDERS:
➢ It is the material added to the formulation to improve the mechanical strength of a tablet.
➢ Addition of binder increases elasticity, which can decrease the tablet strength because of
breakage of bonds as compaction pressure is increased.
➢ Eg: Gelatin, Cellulose derivatives, Polyvinyl pyrrolidine, Starch, Sucrose, etc.,
6. ENTRAPPED AIR:
➢ Presence of entrapped air will cause the tablet to break easily.
7. POROSITY:
➢ Large size particles subjected to light compression will produce highly porous low tablet
strength.

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 COMPACTION PROFILES
❑ Many attempts have been made to minimize the amount of applied force transmitted radially to the die
walls. All such studies lead to characteristic curves called as compaction profiles.
❑ Radial pressure is developed due to attempt of material to expand horizontally.
❑ The plot of radial pressure against axial pressure is called compaction profile.
❑ When the elastic limit of the material is high, elastic deformation may make the major contribution and on
removal of the applied load, the extent of elastic relaxation depends on the value of material modulus of
elasticity(Young’s module)
❑ Lower the modulus, higher will be elastic relaxation, where will be the risk of structural failure.
❑ Higher modulus results in a small dimensional change on decompression hence lesser risk of structural
failure.
❑ Maximum compressional force levels are particularly required in such cases since most of the stored
energy is released on removal of applied load.
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FIGURE:

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1. FORCE-DISPLACEMENT PROFILES
1. The relationship between upper punch force and upper punch displacement during compression, often
referred to as force-displacement profile, has been used as a means to derive information on the compression
behavior of a powder and to predict its tablet forming ability.
2. The area under a force-displacement curve represents the work or energy involved in the compression
process.
3. Different procedures have been used to analyze the curves. One suggested approach is based on the division
of the force-displacement curve into different regions (denoted El, E2 and E3 in Figure)
4. It has been suggested that the areas of El and E3 should be as small as possible if the powder will perform
well in a tableting operation and give tablets of a high mechanical strength.
5. An alternative proposed approach is based on mathematical analysis of the force-displacement curve from
the compression phase, Eg: in terms of a hyperbolic function.

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6. Force-displacement curves have some use in pharmaceutical development as an indicator of the tablet-
forming ability of powders, including the assessment of the elastic properties of materials from the
decompression curve.
7. It can also be used as a means to monitor the compression behavior of a substance in order to document
and evaluate reproducibility between batches.
8. However, the interpretation of the force-displacement relationship in terms of mechanisms of particle
compression, or compression mechanics, is not clarified, which limits the use of force-displacement curves
in fundamental compression studies.
9. Force-displacement measurements have also been used in fundamental studies on the energy conditions
during compaction of powders, i.e. a thermodynamic analysis of the process of compact formation.
10.The energy applied to the powder can be calculated from the area under the force-displacement curve.
11.This compaction energy is used to overcome friction between particles, to deform particles both
permanently and reversibly, and to create new particle surfaces by fragmentation.
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12.The thermal energy released during compaction can be assessed by calorimetry, i.e. the die is constructed as a
calorimeter.
13.The heat released during compression is the result of particle deformation i.e. energy is consumed during
deformation and thereafter partly released when the deformation is completed and the result of the formation
of inter-particulate bonds.
14.Data have been reported indicating that the net effect of a compaction process is exothermal, i.e. more
thermal energy is released during compaction than is applied to the powder in terms of mechanical energy.
15.The main explanation for this is released bonding energy in the form of heat due to the formation of bonds
between particles.
16.At a given fmax the displacement area of plastic deformation is more when compared to the displacement area
of elastic deformation.

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FIGURE: Force –www.DuloMix.com
displacement curve 57
 NWC = GWC –WER
GWC = Wf + Wp + We +Wfr
Where,
NWC = net work of compaction
GWC = gross work of compaction
WER = work of elastic relaxation
Wf = work against friction
Wp = work of plastic deformation
We = work of elastic deformation
Wfr = work of fragmentation

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2. FORCE- TIME PROFILE
Compression force-time profiles are used to characterize the compression behavior of the active
ingredients and excipients.
On a rotary tablet press, the force-time curves are segmented into 3 phases
a) Compression phase: Horizontal and vertical punch movement. Compression is the process in
which maximum force is applied on powder bed in order to reduce its volume
b) Dwell phase: Only horizontal punch movement. When compression force reaches a maximum
value, this maximum force is maintained for prolonged period before decompression.
The time period between the compression phase and decompression phase is known as Dwell time.
c) Decompression phase: Both punches moving away from upper and lower surfaces. Removal of
applied force on powder bed i.e., both punches moving away.

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FIGURE: Compression force-time profile 60
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➢ Compression phase is small for powders having high density (low volume due to less
void spaces). Eg: Dicalcium phosphate dihydrate.
➢ Compression phase is large for powders having low density (more volume due to
more void spaces). Eg: Microcrystalline cellulose.
➢ Plastic materials show a decrease in force over dwell time, in contrast, a plateau is
obtained for brittle materials.
➢ The dwell phase coefficient can be used to measure the plasticity of a substance
mixture.

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Compression event is divided into series of time periods:
➢ Consolidation time: Time period to reach maximum force
➢ Dwell time: Time at maximum force
➢ Contact time: Time for compression and decompression
➢ Ejection time: Time during which ejection occurs
➢ Residence time: Time during which the formed tablet is within the die

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3. DIE WALL FORCE PROFILE:
During tableting , friction arises between the material and the die wall and also
between the particles (inter-particulate friction).
Internal friction is significant only during particle slippage and rearrangement at low
applied pressures.
The coefficient of frictions related to tableting processes are:-
a) Static friction (force required to initiate sliding)
b) Dynamic friction (force required to maintain sliding between two surfaces)
Static friction ( µ1 ) = maximum axial frictional force/ maximum radial force.
Dynamic friction ( µ2 ) = ejection force/ residual die wall force.
Lubrication ratio (R value) is the ratio of the maximum lower punch force to the
maximum upper punch force. www.DuloMix.com
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 The die wall force reaches a maximum just after the maximum upper and lower force
and a constant residual value after upper and lower punch forces become zero. When the
ejection process starts, it increases again.
The residual die wall force is the average of values in the constant region at zero upper
punch force. The difference of displacement between upper and lower punch gives a
measure of the tablet area contact with the die wall.
The high die wall force during ejection is a sign of adhesion of powders to the die.

S. No Material Residual die wall force

1 Plastic Large
2 Brittle Medium
3 Elastic Low
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4. TABLET VOLUME-APPLIED PRESSURE PROFILES
• In both engineering and pharmaceutical sciences, the relationship between volume and applied
pressure during compression is the main approach to deriving a mathematical representation of
the compression process. A large number of tablet volume-applied pressure relationships exist.
• The latter approach is more common as it can be performed rapidly with a limited amount of
powder.
• Among these, the most recognized expression in both engineering and pharmaceutical science is
the tablet porosity-applied pressure function according to Heckel.
HECKEL EQUATION:
▪ Tablet porosity can be measured either on an ejected tablet or on a powder column under load,
i.e. in die. A problem might be that the compression time is different at each pressure, which
could affect the profile for materials having pronounced time-dependent compression behaviour.
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▪ The compression of a powder can be described in terms of a first-order reaction where the pores
are the reactant and the densification is the product.
▪ Based on this assumption, the following expression was derived:
ln (1/E) = KP+E
where
E is the tablet porosity,
P the applied pressure,
A a constant suggested to reflect particle rearrangement and fragmentation,
K the slope of the linear part of the relationship which is suggested to reflect the deformation
of particles during compression.
▪ The reciprocal of the slope value K is often calculated and considered to represent the yield stress
or yield pressure (Py) for the particles, i.e.: ln (1/E) = P/Py+A
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The yield stress is defined as the stress at which particle plastic deformation is initiated.
To be able to use the Heckel yield pressure parameter to compare different substances, it is important to
standardize the experimental conditions, such as tablet dimensions and speed of compaction.

This often shows an initial curvature (phase I) which has been

suggested to reflect particle fragmentation and repositioning.
Thereafter, the relationship is often linear over a substantial range of
applied pressures (phase II), and thus obeys the expression. From the
gradient of this linear part the yield pressure can be calculated, which
is thus a measure of the particle plasticity. Finally, during
decompression an expansion in tablet height is represented by
increased tablet porosity (phase III). From this decompression phase,
a measure of the particle elasticity can be calculated as the relative
change in tablet porosity or height.
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TYPES OF HECKEL PLOTS:
TYPE A: For plastic deforming bodies
It is possible to distinguish the three different
types of powder behaviour by compressing
different size fractions of the same material.
For plastically deforming materials the Heckel
plots, drawn from different size fractions
remain parallel over the entire pressure range.
Eg: Sodium chloride, MCC, Starch.

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TYPE B
For type B materials, there is an
initial curved region followed by a
straight line. This indicates that the
particles are fragmenting at the early
stages of the compression process i.e.,
brittle fracture precedes plastic flow.
In these fragmenting materials, the
plots become coincidental as the
compression pressure increases.
Eg: Lactose, Sucrose
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TYPE C
After initial linear part the plots
become coincidental because the
material packing fraction approaches
unity at quire low compressive stress
level.
Eg: Fatty acids or Lactose mixed
with high percentage of fatty acids.

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Significance of Heckel plots:
1. The Heckel constant K has been related to the reciprocal of the mean yield pressure, which is the
minimum pressure required to cause deformation of the material under compression.
2. The intercept of the curve portion of the curve at low pressure represents a value due to
densification by particle rearrangement.
3. The intercept obtained from the slope of the upper portion of the curve is a reflection of the
densification after consolidation.
4. A large value of the Heckel constant indicates the onset of plastic deformation at relatively low
pressure.
5. A Heckel plot permits an interpretation of the mechanism of bonding.
6. The crushing strength of tablets can be correlated with the values of k of the Heckel plot; larger k
values usually indicate harder tablets.
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Limitations:
1. Shape of the plot is very sensitive for small errors in the determination of powder true
density.
2. Linear part of the plot is sometimes difficult to determine.
3. Heckel plot determination requires very accurate data. Even the deformation of the tablet
compression machine has to be recorded.
Heckel plots are influenced by:
• Residual porosity in particular formulations.
• Overall time of compression.
• Degree of lubrication.
• Size of the die.
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 COMPRESSION EQUATIONS
1. KAWAKITA EQUATION
➢ A promising means of assessing the compression mechanics of granules is to calculate a compression
shear strength from the Kawakita equation.
➢ This was derived from the assumption that, during powder compression in a confined space, the system
is in equilibrium at all stages, so that the product of a pressure term and a volume term is constant.
➢ The equation can be written in the following linear form:

𝑷 𝟏 𝑷
= +
𝑪 𝒂𝒃 𝒂
➢ where P is applied pressure,
C the degree of volume reduction of a powder compact
a is total volume reduction for the powder bed (Carr’s index)
b is constant that is inversely elated to the yield strength of the particles
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➢ The degree of volume reduction relates the initial height of the powder column (h0) to the height
of the powder column (the compact) at an applied pressure P (hp) as follows:

➢ C = (ho-hp)/ho
➢ The equation has been applied primarily to powders of solid particles.
➢ However, it has been suggested that the compression parameter 1/b corresponds to the strength
of granules in terms of a compression strength.
➢ The procedure thus represents a possible means to characterize the mechanical property of
granules from a compression experiment.
➢ This equation holds best for soft fluffy pharmaceutical powders, and is best used for low
pressures and high porosity situations.
➢ It is a modification of the Heckel equation.

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2. HECKEL EQUATION:
➢ It is based on the assumption that densification of bulk powder
under force follows first order kinetics.
➢ The Heckel equation is expressed as,
ln [1/(1-D)] = KP +A
Where,
D = relative density of the powder
P = applied pressure
K = constant, measure of the plasticity of a compressed
material
A = constant, die filling and particle rearrangement before
deformation.

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➢ In 1961, Heckel proposed a relationship between the constant K and the yield strength for a range of metal
powders.
K = 1/3 σ
➢ Where σ is the yield strength of the material. K is inversely related to the ability of the material to deform
plastically.

3. WALKER EQUATION
➢ The walker equation is based on the assumption that he rate of change of pressure with respect to volume
is proportional to the pressure, thus giving a differential equation.
➢ Log P = - L * V’/V0 +C1
➢ Where Vo is the volume at zero porosity.
The relative volume is V’/Vo = V = 1/D
C1 is constant
➢ The coefficient L is referred to as the pressing modulus
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 SOLUBILITY
Solubility is defined as amount of solute that can be dispersed molecularly in the given
amount of solvent to give a homogenous mixture under standard conditions of
temperature, pressure and pH.
❖ Test for solubility is used to identify the purity of the drug substance.
IMPORTANCE OF SOLUBILITY
➢ Therapeutic efficacy of a drug depends upon bioavailability and ultimately depends
upon solubility.
➢ Solubility is one of important parameter to achieve desired concentration of drug in
systemic circulation.
➢ Only 8% of new drug candidates have high solubility and high permeability.
➢ 40% of drugs of new drug entitieswww.DuloMix.com
are poorly water soluble. 78
Method of determination of solubility:
An excess powder is added in the solvent to achieve the saturated solubility and constant stirring is
given for long duration at required temperature till the equilibrium is achieved. There should be few amount
of undissolved solute should be present in order to ensure that the solvent is saturated. The aliquot of the
saturated solution is taken separated from the undissolved solute by specific method. Generally speaking,
filtration is the common method employed for most of the studied.

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FACTORS AFFECTING SOLUBILITY
1. Solubility of solids in liquids:
➢ Temperature
➢ Particle size
➢ Molecular structure modifications
➢ Common ion effect
➢ Effect of complex formation
➢ Effect of surfactants

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2. Solubility of liquids in liquids:
➢ Complete miscibility
➢ Practically immiscible
➢ Partially miscible
3. Solubility of gases in liquids:
➢ Effect of pressure
➢ Effect of temperature
➢ Salting out
➢ Effect of chemical reactions

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BIOPHARMACEUTICAL CLASSIFICATION SYSTEM:
BCS is a scientific framework for classifying drug substances according to their aqueous
solubility and their internal permeability.

Class Solubility Permeability Absorption Rate-Limiting Step in Drug

Pattern Absorption Examples

I High High Well absorbed Gastric emptying Diltiazem

II Low High Variable Permeation Nifedipine

III High Low Variable Dissolution Insulin

IV Low Low Poorly absorbed Case to case Taxol

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ABSOLUTE OR INTRINSIC SOLUBILITY:
It is defined as the maximum amount of solute dissolved in a given solvent under
standard conditions of temperature, pressure and pH. It is a static property.

TECHNIQUES OF SOLUBILIZATION:
Solubilization is the technique by which the desired solubility of a poorly water-soluble
substance is achieved. Since, water is the most commonly used solvent in pharmaceutical
liquids, the following techniques have been aimed at increasing the solubility of a drug
substance in water.

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SOLUBILITY ENHANCEMENT TECHNIIQUES
A. Pharmaceutical approaches
1. pH Adjustments
(a) Salt formation.
(b) Addition of buffers to the formulation.
2. Cosolvency
3. Complexation
4. Surface active agents
5. Hydrotopism
6. Micronization
7. Solid solutions
B. Chemical modifications www.DuloMix.com
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Pharmaceutical Approaches
1. pH Adjustments:
Most of the drugs are either weak acids or weak bases. The aqueous solubility of a
weak acid or a weak base is greatly influenced by the pH of the solution.. The solubility of
a weak base can be increased by lowering the pH of its solution whereas the solubility of a
weak acid can be improved by increasing the pH. pH adjustment for improving the
solubility can be achieved in two ways:
(a) Salt formation.
(b) Addition of buffers to the formulation.
Eg. Gatifloxacin is insoluble in water at higher pH but the same drug get solubilized at the
lower pH and attends maximum solubility below the pH of 5. Hence the parenteral
preparation of Gatifloxacin is formulated at the pH of 3.5 to 5.5.
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2. Cosolvency:
Cosolvency is the technique of increasing the solubility of poorly soluble drugs in a liquid by
addition of a solvent miscible with the liquid in which the drug is also highly soluble. Cosolvents such
as ethanol, glycerol, propylene glycol or sorbitol decreases the interfacial tension or alter the dielectric
constant of the medium and increases the solubility of weak electrolytes and non-polar molecules in
water. Eg: Formulation of Diazepam injection using Propylene glycol as cosolvent.
3. Complexation:
In certain cases, it may be possible to increase the solubility of a poorly soluble drug by allowing
it to interact with a soluble material form a soluble intermolecular complex. It is however essential
that the complex formed is easily reversible so that the free drug is released readily during or before
contact with biological fluids. A number of compounds, such as Nicotinamide and Beta-cyclodextrin,
have been investigated as possible agents to increase the solubility of water insoluble drugs.
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Eg. Interaction of Iodine with Povidone to form water soluble complex and preparation of Itraconazole
injection by forming inclusion complex of Itraconazole with Hydroxy propyl beta cyclodextrin.
4. Surface active agent:
A surface active agent is a substance which reduces the interfacial tension between the solute and the
solvent to form thermodynamically stable homogeneous system. The mechanism involved in this
solubilization technique involves micelle formation and due to formation of stable system it is widely used
in pharmaceutical formulations. When a surfactant having a hydrophilic and a lipophilic portion is added
to a liquid, it first accumulates at the air/solvent interface; further addition leads to its dispersion
throughout the liquid bulk. At a certain concentration known as the Critical Micelle Concentration (CMC),
the dispersed surfactant molecules tend to aggregate into groups of 100 to 150 molecules known as
micelle.
Eg: Fat soluble vitamins A, D, E and K, antibiotics like Griseofulvin and Chloramphenicol and analgesics
such as Aspirin and Phenacetin have been solubilized by using surface active agents.
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5. Hydrotropism
Hydrotropism is the term used to describe the increase in aqueous solubility of a drug by the use of large
concentrations (20% to 50%) of certain additives. The exact mechanism for hydrotropism is not clear although
complexation, solubilization or cosolvency have been suggested as the probable mechanisms. Hydrotropism is
rarely applied to pharmaceutical formulations, as the increase in aqueous solubility is generally inadequate.
Eg: Increase in solubility of Caffeine and Theophylline by addition of Sodium benzoate and sodium salicylate
respectively.
6. Micronization
Surface area and particle size are inversely related to each other. Smaller the drug particle, larger the
surface area and greater is the solubility. A decrease in particle size achieved through micronization, will result
in higher solubilization of drug.
Eg: Micronization of poorly aqueous soluble, but non-hydrophobic drugs such as Griseofulvin and
Chloramphenicol results in enhanced solubility.
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7. Solid Solutions:
Solid solutions are prepared by melting of physical mixture of solute, a poorly
water soluble drug and solid solvent, a highly water soluble compound or polymer
followed by rapid solidification. Solid solutions are also called as molecular
dispersions or mixed crystals.
Eg: Griseofulvin from Succinic acid solid solution dissolves 6 to 7 times faster than
pure Griseofulvin and Digitoxin-PEG 6000 solid solution showed enhanced solubility.

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Chemical Modification
Solubility of a substance can be improved by chemically modifying the substance. For
example, aqueous solubility can be improved by increasing the number of polar groups in a
molecule. This is often achieved by salt formation; for instance, alkaloids are poorly soluble in
water whereas alkaloidal salts are freely soluble in it. Alternatively, a molecule may be modified
to produce a new chemical entity or prodrug.
Eg: The aqueous solubility of Chloramphenicol sodium succinate is about 400 times greater than
that of Chloramphenicol. Prodrugs, however, must revert to parent molecule after administration.
Stability
In addition to the solubility of the medicament, other considerations regarding physical,
chemical and microbiological stability of the preparation will need to be taken into consideration.

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 REFERENCES
1. Pharmaceutical dosage forms – Tablets by Herbert A Lieberman, Leon Lachman and Joseph B
Schwartz. Volume 2. Pg no.201-241.
2. The theory and practice of Industrial Pharmacy by Leon Lachman, Herbert A Lieberman, Joseph L.
Kanig special Indian edition 2009, Pg no:71-83
3. Aulton’s Pharmaceutics-The design and manufacturing of machines. 3rd edition. Pg no176-177.
4. C.V. Subrahamanyam Textbook of Physical Pharmaceutics, 2nd edition, Vallabh Prakashan, Delhi. Pg
no.180-234
5. Text book of pharmaceutical dosage forms: tablets. 3rd edition. edited by Larry L. Augsburger, Stephen
W. Hoag. Pg no.555.
6. Modern Pharmaceutics by Gilbert. S. Banker, Christopher T. Rhodes, 4th edition, Pg no:408-409.
7. D.M. Brahmankar, S.B. Jaiswal; Bio pharmaceutics & Pharmacokinetics- A treatise, 6th edition, Vallabh
Prakashan.
8. A Text Book of Pharmaceutics – 1 by Dr. Sanjar Alam, 3rd edition, Pg no: 2.32 – 2.36. 91
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